We have focused on pharmacological augmentation of fetal hemoglobin levels in sickle cell patients. In particular, hydroxyurea (HU), a cell-cycle specific agent that blocks DNA synthesis by inhibiting ribonucleotide reductase, has been shown to increase fetal hemoglobin (HbF) levels in some patients with sickle cell disease, although the mechanism of action remains to be defined. In order to develop protocols for effective treatment of sickle cell patients, we have studied the effects of HU administration on ten hospitalized patients treated on an escalating dose schedule for periods of three months. Of the ten patients, 7 were considered responders by virtue of at least a two-fold increase in the %F-reticulocytes and a concomitant two-fold rise in %HbF. Among the responders, HbF levels increased 2 to 10-fold, generally after a lag period of about 40 days (range10 to 65 days). Three patients achieved levels of HbF of 10 to 15%. The initial values of HbF, F-retics, the degree of anemia or the specific beta-globin gene haplotype were not predictive of response. Statistical analysis of the three cellular variables that determine HbF levels in these patients disclosed that HbF production, as estimated by F-retic number, accounted for about 70% of the increase in HbF. Four of the responders were retreated with optimal HU dose after a " washout" period and were found to have greater HbF responses, again occurring after a measurable lag period. Treatment with daily doses of hydroxyurea, as opposed to treatment on 4 out of seven days, or blood transfusions appear to blunt the maximal HbF response. This prolonged lag period prior to response, as well as the effects of transfusion and daily therapy suggests that mechanisms other than acute cytoreduction with regeneration, such as changes in mechanisms controlling gamma-globin gene transcription may be operative in the increased HbF synthesis. Should a significant sustained F-cell response in select patients while on HU, it may be possible to increase further the magnitude of the response by simultaneously administering short courses of cloned human erythropoietin or cloned granulocyte-macrophage colony stimulating factor. In this fashion, one may approach fetal hemoglobin levels consonant with those observed in the benign HBS-HPFH phenotypes.